Annals of Oncology Advance Access originally published online on November 1, 2006
Annals of Oncology 2007 18(2):305-310; doi:10.1093/annonc/mdl392
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© 2006 European Society for Medical Oncology
gastrointestinal tumors |
Phase II trial of capecitabine and oxaliplatin (CAPOX) plus cetuximab in patients with metastatic colorectal cancer who progressed after oxaliplatin-based chemotherapy
1 Department of Medical Oncology, University General Hospital of Heraklion, Heraklion, Crete, Greece
2 Department of Pathology, University General Hospital of Heraklion, Heraklion, Crete, Greece
3 Department of Radiology, University General Hospital of Heraklion, Heraklion, Crete, Greece
* Correspondence to: Dr V. Georgoulias, Department of Medical Oncology, University General Hospital of Heraklion, PO Box 1352, Heraklion 71110, Crete, Greece. Tel: +30-2810-392802; Fax: +30-2810-392802; E-mail: georgsec{at}med.uoc.gr
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Abstract |
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Background: Cetuximab is an IgG1 monoclonal antibody targeting the epidermal growth factor receptor and is able to reverse the resistance to irinotecan in patients with metastatic colorectal cancer (mCRC). This phase II trial evaluates the safety and efficacy of cetuximab combined with capecitabine and oxaliplatin (CAPOX) in the treatment of patients with mCRC progressing under oxaliplatin-based chemotherapy.
Patients and treatment: Forty patients with mCRC were treated with cetuximab (loading dose 400 mg/m2 and then 250 mg/m2 i.v. weekly) in combination with CAPOX (d1: L-OHP 85 mg/m2 and d1–7 capecitabine 2000 mg/m2 every 2 weeks). Thirty-one (77.5%) and nine (22.5%) patients had oxaliplatin-refractory and -resistant disease, respectively; in addition, 32 (80%) patients had also progressed on prior irinotecan-based chemotherapy.
Results: One hundred and thirty-four cycles were administered (median of four cycles per patient). Main toxic effects included grade 3–4 neutropenia (12.5%), grade 3/4 diarrhea (7.5%), grade 3 fatigue (2.5%), and grade 2–3 neurotoxicity (22.5%). One (2.5%) complete and seven (17.5%) partial responses were achieved [overall objective response rate (ORR): 20%; 95% confidence interval (CI): 9% to 32%)], whereas 11 (27.5%) patients had stable disease [disease control rate (DCR): 47.5%; 95% CI: 30.2% to 64.5%]. The ORR and DCR were 18.7% and 46.8%, respectively, in patients with oxaliplatin-refractory disease. The median time to tumor progression was 3 months, the median survival 10.7 months and the probability of 1-year survival rate 53.4%.
Conclusions: The combination of cetuximab plus CAPOX is safe and has a promising activity in patients with mCRC refractory or resistant to oxaliplatin.
Key words: cetuximab, colorectal cancer, oxaliplatin-resistant
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Colorectal cancer (CRC) is a major cause of morbidity and mortality worldwide [1]. Palliative treatment of metastatic colorectal cancer (mCRC) is based on the use of chemotherapy with the anticancer drugs 5-fluorouracil, irinotecan (CPT-11), and oxaliplatin (L-OHP). During the last few years, the median overall survival (OS) of patients with advanced CRC has been substantially increased from 12 months to about 21–22 months when all of the three available chemotherapeutic agents have been administered [2, 3]. In a recent meta-analysis of seven phase III trials in advanced CRC, it was shown that the median OS was significantly correlated with the proportion of patients receiving all active agents during the disease course [4]. However, the treatment options for mCRC patients with disease refractory to all three antitumor drugs are limited. The development of rationally designed targeted anticancer agents further improved treatment's outcome. Indeed, the addition of the anti-vascular endothelial growth factor antibody bevacizumab to irinotecan-based frontline chemotherapy is associated with an improved time to tumor progression (TTP) and OS [5].
Furthermore, the epidermal growth factor receptor (EGFR) is the archetypal member of a receptor tyrosine kinase family composed of four closely related receptors called HER1 (EGFR), HER2, HER3 and HER4 [6]. Expression or up-regulation of the EGFR gene occurs in 60% to 80% of colorectal tumors [7]. Aberrant activation of this highly regulated signaling pathway is believed to contribute to enhanced cellular proliferation, inhibition of apoptosis, tumor cell invasion and metastasis [8].
Cetuximab (Erbitux®) is a chimeric IgG1 monoclonal antibody that binds to EGFR with high specificity and affinity, thus blocking ligand-induced phosphorylation of EGFR. Preclinical studies of cetuximab showed excellent antitumor activity. Synergistic activity was seen with a number of anticancer drugs and especially with irinotecan [9], platinum derivates [10] and radiotherapy [11]. Preclinical models indicate that tumor cells with EGFR aberrant activation have increased DNA repair capacity [12–14]. In addition, preclinical data demonstrated a synergism between oxaliplatin and cetuximab [15].
Cetuximab has shown its antitumor activity in patients with mCRC progressing under irinotecan-based chemotherapy irrespective of the membrane expression of EGFR [16, 17]. Cunningham et al. [18] have also reported that in patients with mCRC who progress under CPT-11-based therapy, the administration of CPT-11 and cetuximab has a higher efficacy than cetuximab alone, in terms of objective response rate (ORR), overall disease control rate (DCR) and TTP.
On the basis of scientific background, we investigate the efficacy and the tolerance of the capecitabine and oxaliplatin (CAPOX) regimen in addition to cetuximab in patients with mCRC who had disease progression under L-OHP-based chemotherapy. We selected the CAPOX regimen given every 2 weeks because it is more convenient for a quite follow-up of the patients [19].
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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patients
Patients with histologically documented metastatic adenocarcinoma of the colon or rectum were enrolled in a prospective phase II trial. Immunohistochemistry expression of EGFR on the primary tumor cells was not mandatory for patients' enrollment. All patients had received either frontline or second-line oxaliplatin-based chemotherapy for metastatic disease (Table 1). Prior treatment with cetuximab was not allowed. Other eligibility criteria were: age
18 years; performance status (World Health Organization) 0–2; at least one bidimensionally measurable lesion of 2 cm; a life expectancy of at least 3 months; adequate hematologic parameters (absolute neutrophil count 1.5 x 109/l and platelets 100 x 109/l); creatinine level and total rise in bilirubin level 
1.25 times the upper limit of normal; aspartate and alanine aminotransferases 3.0 times the upper limit of normal; absence of active infection or malnutrition and absence of a second primary tumor. Patients with peripheral neuropathy that exceed grade 1 were considered, or those with severe cardiac dysfunction, liver metastases involving >50% of the liver parenchyma, chronic diarrhea or prior irradiation affecting >30% of the active bone marrow were excluded. The study was approved by the Ethics and Scientific Committees of our institution. All patients gave written informed consent in order to participate in the study.
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chemotherapy
L-OHP (Eloxatin; Sanofi-Aventis, Collegeville, PA) was administered on day 1 at the dose of 85 mg/m2 as a 2-h i.v. infusion. For prevention of severe neurotoxicity, calcium gluconate (1 g) and magnesium sulfate (1 g) were administered i.v. for a period of 15 min just before the L-OHP infusion and repeated at the same dose after the completion of the L-OHP infusion [20]. Capecitabine (Xeloda; Roche Laboratories Inc., Nutley, NJ) was administered orally, at the dose of 2000 mg/m2 twice daily from d1 to d7. The chemotherapy cycle was repeated every 2 weeks. Cetuximab (Erbitux®; Merck, Germany) was given at a loading dose of 400 mg/m2 by a 2-h i.v. infusion on d1. Premedication with diphenhydramine 50 mg i.v. was used. Cetuximab was then further administered on a weekly basis at a dose of 250 mg/m2. Routine antiemetic prophylaxis with a 5-hydroxytryptamine-3-receptor antagonist was used. Treatment was administered until disease progression or unacceptable toxicity or until the patient declined further treatment.
Patients were assessed for toxicity before each cycle using the National Cancer Institute Common Toxicity Criteria Version 3.0 [21]. Peripheral sensory neuropathy was graded according to the L-OHP-specific scale modified from Caussanel et al. [22].
dose adjustment
Chemotherapy was delayed until recovery if neutrophils were <1.5 x 109/l, platelets were <100 x 109/l, or for significant persisting non-hematologic toxicity. Doses of L-OHP and capecitabine were reduced by 15% in subsequent cycles in case of grade 4 neutropenia or grade 3–4 thrombocytopenia lasting for >3 days or in case of febrile neutropenia. No prophylactic administration of granulocyte colony-stimulating factor was allowed. In the case of grade 3–4 diarrhea, stomatitis or ‘hand and foot’ syndrome, the doses of capecitabine were reduced by 15% in subsequent cycles. The L-OHP dose was reduced by 15% in case of persistent (14 days) paresthesias or temporary (7–14 days) painful paresthesias or functional impairment. In cases of persistent (14 days) painful paresthesias or functional impairment, L-OHP was omitted from the regimen in subsequent cycles until recovery to grade 1, when it was restarted with a dose reduced by 15%. The administration of cetuximab was delayed for 1 week in case of grade 3–4 skin toxicity and, then, restarted at a reduced dose by 15%. Cetuximab was discontinued in cases of hypersensivity reaction or occurrence of skin toxicity grade 3, or in case of dose delay for more than three consecutive weeks because of severe skin toxicity [23].
patient evaluation
Pretreatment evaluation included a detailed medical history and physical examination, a complete blood cell count (CBC) with differential and platelet count, whole-blood chemistry and computed tomography (CT) scans of the chest and abdomen. Pretreatment evaluation had to be carried out within 2 weeks before study entry. EGFR status of the tumor was determined by immunohistochemical analysis of paraffin-embedded tumor specimens with the use of an EGFR diagnostic kit (Dako Cytomation, Glostrup, Denmark). During treatment, a CBC was carried out weekly, and in case of grade 3–4 neutropenia, thrombocytopenia or febrile neutropenia, it was carried out daily until hematologic recovery. In addition, patients were clinically assessed and routine biochemical tests were carried out before each treatment cycle in order to assess tumor evolution and treatment toxicity. Response to treatment was evaluated after four 2-week cycles (2 months) or sooner if clinically indicated.
The Response Evaluation Criteria in Solid Tumors were used to assess tumor responses [24]. All objective responses were required to be confirmed by a follow-up CT scan at least 4 weeks following documentation of the response.
Patients who had presented tumor progression under treatment with L-OHP-based chemotherapy or within 3 months from the end of chemotherapy were considered to have L-OHP-refractory disease. Patients who achieved an objective response or disease stabilization under L-OHP-based chemotherapy but presented disease progression after 3 months from the end of chemotherapy were considered to have L-OHP-resistant disease [25].
statistical considerations
The primary end point of the study was the ORR. The study followed the optimal Simon two-step design. If a minimum ORR of 10% was observed in the first 16 patients, an additional 24 patients should be enrolled (
= 0.05, power 80%). Secondary objectives were the treatment's tolerance, the response duration (RD), TTP and the OS time. RD was measured from the first documentation of response to disease progression. The TTP was determined by the interval between the initiation of treatment and the date when disease progression was first documented or the date of death from any cause. OS was measured from the date of treatment initiation to the date of death. The follow-up time was measured from the day of first treatment administration to the time of the study's cut-off date (for alive patients). TTP and OS were estimated by the Kaplan–Meier method [26], and the confidence intervals (CIs) for response rates were calculated using methods for exact binomial CIs [27].
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patients' characteristics
From April 2004 to September 2005, 40 patients with mCRC were enrolled. Thirty-one (77.5%) patients were refractory to prior L-OHP-based chemotherapy, while nine (22.5%) were resistant. Prior L-OHP-based chemotherapy consisted of the following: frontline FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin) in eight (20%) patients, frontline FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan) in two (5%) patients, second-line FOLFOX in four (10%) patients and second-line XELOX [Xeloda (capecitabine), oxaliplatin] in 26 (65%) patients (Table 1). The CAPOX plus cetuximab regimen was administered as second-line treatment in 10 (25%), as third-line in 22 (55%) and as fourth-line in eight (20%) patients. Thirty-two (80%) patients had received prior treatment with CPT-11-based regimens. Patients' characteristics are presented in Table 1. The median time elapsed between the documentation of disease progression and study entry was 2.2 months (range 1–3). All patients were assessable for toxicity and response to treatment.
compliance with treatment
Two hundred and twenty-six chemotherapy courses were administered (median: four courses per patient, range 2–18). Eighteen (7.9%) courses were delayed for a median of 4 days (range 1–7) because of non-hematologic (n = 11; 4.8%) toxicity, and for reasons unrelated to disease or treatment (n = 7; 3.1%). The median interval between cycles was 16 days (range 14–20). Dose reduction of cytotoxic agents was required in 10 (4.4%) cycles because of non-hematologic toxicity whereas in five (2.2%) cycles the dose of cetuximab was reduced because of grade 3 skin rash. The delivered relative dose intensity was 89%, 92% and 96% of the protocol-planned doses for L-OHP, capecitabine and cetuximab, respectively. At the time of analysis, 35 (87.5%) patients had discontinued treatment for the following reasons: progressive disease (PD) (n = 30 patients), unacceptable neurotoxicity (n = 2 patients), whereas, three additional patients refused further treatment after they had received 12 chemotherapy cycles; two of these patients achieved a partial response (PR) and one stable disease (SD) after six cycles of chemotherapy without any further shrinkage in the tumor lesions with additional chemotherapy cycles.
treatment's efficacy
In an intention-to-treat analysis, one (2.5%) patient achieved a documented complete response (CR) and seven (17.5%) a PR for an ORR of 20% (95% CI 12.7% to 32.4%). In addition, 11 (27.5%) patients had SD and 21 (52.5%) PD. The DCR (CR + PR + SD) was 47.5%. The site-specific response rate (RR) was as follows: 25% for lymph nodes, 22.5% for liver metastases, 17.5% for lung metastases and 15% for adrenal metastases. The median RD was 4.9 months (range 1.6–8.9) and the median TTP 2.9 months (range 0.5–9.8) (Figure 1). After a median follow-up period of 8.1 months (range 0.5–16.7), 22 (55%) patients were still alive. The median OS was 10.7 months for all patients; however, the median OS was 7.7 (range 0.5–14.0) months for patients with PD, while it has not yet been reached for patients with disease control (range 1.3–16.7 months; P = 0.0016) (Figure 2).
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The subgroup analysis revealed that an objective response was achieved in five (16.1%) out of 31 patients who were considered refractory to prior L-OHP-based chemotherapy, while eight (25.8%) additional patients presented disease stabilization (DCR 42%); the median TTP was 2.6 months (range 1.5–9.8 months) and the median OS 10.5 months (range 1.3–14.8 months). The probability of response did not correlate with prior CPT-11-based chemotherapy or the line of chemotherapy. Also, there was no correlation between the degree of EGFR expression and response to treatment (Table 2). A higher but not significant RR was observed in patients with skin rash compared with those without rash (25.7% versus 8.3%, respectively; P = 0.160).
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Although, salvage treatment was not specified by the protocol, the various chemotherapy regimens used in this setting were also evaluated. Twenty-one (52.5%) patients had received salvage treatment with CPT-11 and cetuximab. Two patients (9.5%) achieved PR and six (28.5%) SD (DCR of 38%); six of these eight patients had previously received CPT-11 (Table 3).
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toxicity
The adverse events are presenting in Table 4. Grade 3–4 diarrhea developed in three (7.5%) patients and grade 2 and 3 fatigue in eight (20%). Neurosensory toxicity (grade 1–2) was observed in 26 (65%) patients and reached grade 3 in two (5%). It is, however, important to mention that 18 (45%) patients had grade 1 neurotoxicity at study entry due to prior L-OHP-based chemotherapy. Cold-induced dysesthesia was reported in 13 (32.5%) patients whereas paresthesia without pain occurred in six (15%) patients. Cumulative paresthesia occurred in six (15%) patients but without functional impairment. The estimated incidence of grade 2–3 neuropathy, attributed to L-OHP exposure, was 6% after 4 cycles and 25% after 12 cycles of chemotherapy.
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The characteristic skin reactions of cetuximab were observed in 34 (85%) patients and were of grade 3 in six (15%) of them. All patients presented skin rash within the first two cycles (1 month) of treatment. Many patients presented some degree of spontaneous partial improvement in the rash during the first 2–3 months of therapy without modification of the cetuximab dose. No correlation between the degree of skin rash and response rate was observed (Table 2). Paronychial cracking were reported in eight (20%) patients and tended to be persistent during the whole period of treatment.
Hematologic toxic effects were mild. Grade 3 neutropenia was observed in one (2.5%) patient. There was no need for hospitalization because of treatment-related toxicity. The death rate within the first 60 days of treatment was 2.5% (95% CI 1.0% to 4.3%).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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To the best of our knowledge, this is the first study evaluating the in vivo reversal of resistance to L-OHP with the addition of cetuximab. In the present study, 77.5% of the enrolled patients were refractory to L-OHP; in addition, 80% of the enrolled patients had also progressed under CPT-11-based chemotherapy. The observed RR (20%), TTP (2.9 months) and OS (10.7 months) were higher in our study compared with those reported with cetuximab monotherapy (RR 9%, TTP 1.4 months and OS 6.4 months) [17, 18]. It is important to mention that the population of this study is more pretreated than the population of the BOND study. Approximately 75% of the patients had previously received three or more chemotherapy schedules compared with 40% in the BOND study [18] and all patients had received the three active drugs. Therefore, it is reasonable to conclude that there is evidence of in vivo synergy between L-OHP-based chemotherapy and cetuximab. The demonstration of a definitive evidence for in vivo synergy, however, requires a randomized study with a design similar to that of the BOND study [18].
A recent in vitro study has demonstrated that irradiation and exposure to cisplatin results in EGFR translocation to the nucleus, where it is localized predominantly in regions with uncoiled chromatin. These regions are easily accessible for DNA repair processes after exposure to genotoxic treatments. Treatment of cells with cetuximab significantly reduced the nuclear transport of the EGFR, and as a consequence, DNA-dependent protein kinase activity and formation of the DNA end-binding complexes were inhibited. These molecular events are associated by impaired DNA repair activity and result at least in reduced clonogenic survival [13].
An interesting observation of the present study is that 21 patients who had disease progression to CAPOX plus cetuximab regimen were treated with CPT-11 plus cetuximab; most of these patients were previously characterized as refractory to both L-OHP and CPT-11. In this particular group of patients with an extremely poor prognosis the ORR to CPT-11 plus cetuximab was 9.5%, the DCR 38%, the TTP 3.7 months and the OS 12.2 months (for the patients treated with CAPOX plus cetuximab followed by CPT-11 plus cetuximab). These results indicate that some of these patients could benefit from this ‘sequential’ approach.
It is noteworthy that these results were obtained with minimal toxicity. The main toxicity of the combination was diarrhea and neurotoxicity. Diarrhea was mild and there was no patient requiring hospitalization. On the other hand, neurotoxicity was the main limiting toxicity of CAPOX plus cetuximab combination. Despite the fact that practically half the enrolled patients presented grade 1 neurosensory toxicity at the time of enrollment because of their previous exposure to L-OHP, only nine patients presented grade 2 and 3 neurotoxicity and treatment discontinuation was required in two of them. A possible explanation for this low incidence of severe neurotoxicity could be the relatively low median number of cycles administered. Alternatively, we cannot exclude that the use of calcium gluconate and magnesium sulfate prevents severe neurotoxicity [20].
In conclusion, the CAPOX plus cetuximab combination is an active and well-tolerated salvage treatment of patients with mCRC refractory or resistant to L-OHP. This phase II study provides preliminary evidence that the addition of cetuximab to L-OHP-based chemotherapy could revert the resistance of tumor cells to L-OHP; however, this observation needs further evaluation in a prospective randomized trial. The results of the present study also emphasize the need for the design of a therapeutic algorithm at the time of initial diagnosis of unresectable mCRC.
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Acknowledgements |
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This work was partly supported by the Cretan Association for Biomedical Research (CABR). JS, AK, NV and APK are recipients of a CABR clinical fellowship.
Received for publication June 28, 2006. Revision received September 13, 2006. Accepted for publication September 14, 2006.
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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